Genomic instability is associated with cancer progression, and defects in DNA mismatch repair (MMR) is one pathway leading to genomic instability. Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in genes encoding proteins involved in MMR, and defects in MMR have also been observed in sporadic cancers. DNA sequence analyses of the alterations in MMR genes in HNPCC kindreds has revealed that more than 25% are missense codons resulting in single amino acid replacements. It is not possible to unambiguously assign these as either mutations or silent polymorphisms without data on the in vivo function of the variant proteins. Phase I research validated the use of functional genetic tests of DNA mismatch repair in yeast to determine the significance of amino acid replacements observed in human MMR proteins. In addition to identification of silent polymorphisms and mutations, certain amino acid replacements were shown to result in altered efficiency of MMR. Phase II research will further develop this technology for the purpose of retrospective and prospective analyses of the functional consequences of amino acid replacements in human MMR proteins. Data generated with this technology will allow accurate interpretation of genetic tests for HNPCC, sporadic cancers and common polymorphisms in MMR genes. PROPOSED COMMERCIAL APPLICATION: Not Available